Chemotherapy in head and neck

Brief notes on cellular kinetics and chemotherapy in head and neck cancer

1. Chemotherapy in Head and Neck Cancer

2. Content Introduction Cell cycle/ tumor biology and chemotherapy Pharmacology of Chemotherapy drugs Chemotherapy treatment modalities Agents used in Head and neck cancer Landmark trials in HNC treatment Summary Reference

3. Introduction The term chemotherapy was coined by Paul Ehlrich It is defined as the use of chemical compounds in treatment of neoplastic diseases so as to destroy offending cancer cells without damaging the host Expansion of the role of chemotherapy in HNSCC Various trials shown that CTRT , brings improvements in locoregional control, organ preservation, and overall survival. Development of novel targeted therapies

4. Doxorubicin 5 fluorouracil Vinblastine Cisplatin Lomustine 5FU Methotrexate Doxorubicin Lomustine 5FU Vincristine Vinblastine Bleomycin Cisplatin Carmustine Doxorubcin

5. Classification of CT drugs Cytotoxic drugs Targeted agents Hormonal agents Alkylating agents Platinum based compound Antimetabolites Microtubule damaging agents Topoisomerase 1 and 2 inhibitors Antibiotic Miscellaneous Tyrosine protein kinase inhibitor EGF receptor inhibitors Angiogenesis inhibitors Proteasome inhibitors Unnamed monoclonal antibody Hormonal drugs Glucocorticoids Estrogens Aromatase inhibitor Antiandrogen 5 Alpha reductase GnRH antagonist Progestin

6. Alkylating Agents Electrophilic alkyl group or a substituted alkyl group can covalently bind to cellular nucleophilic sites. Discovered during the World war I- Mustard gas had vesicant property Mechlorethamine – first alkylating agent used in human cancer treatment Most alkylating agents cause dose related bone marrow toxicity and intestinal mucosa injury.

7. Alkylating agents Class Examples ALKYL SULPHONATES BUSULFAN , BENDAMUSTINE ETHYLENEIMINES / METHYLMELAMINES THIOTEPA , ALTRETAMINE NITROGEN MUSTARD MECHLORETHAMINE , MELPHALAN,CHLORAMBUCIL , CYCLOPHOSPHAMIDE, IFOSFAMIDE NITROSOUREA CARMUSTINE , STREPTOZOTOCIN TRIAZENES DACARBAZINE

8. Platinum based compounds Discovered during 1961 by Dr. Barnett Rosenberg accidently from his work on effect of electromagnetic radiation on bacteria Cis- diamminedichloroplatinum (II) (cisplatin) cis- diamminecyclobutanedicarboxylato platinum (II) (carboplatin) 1,2-diaminocyclohexaneoxalato platinum (II) ( oxaliplatin ) nedaplatin (Japan), lobaplatin (China)

9. Antimetabolites Reduced folates play a central role in one-carbon metabolism, as they are essential for the biosynthesis of purines, thymidylate, and protein Antimetabolites block either the synthesis or mimic action of certain DNA substrates Aminopterin was the first antimetabolite -1940 Targets multiple enzymes involved in folate metabolism Thymidylate synthase ( TS ), dihydrofolate reductase ( DHFR ), glycinamide ribonucleotide (GAR) formyltransferase , and aminoimidazole carboxamide ( AICAR ) formyltransferase

10. Antimetabolites CLASS EXAMPLE ANTIFOLATES METHOTREXATE, PEMETREXED , PRALATREXATE FLUROPYRAMIDINES 5-FU CAPECITABINE TAS-102 DEOXYCYTIDINE ANALOGS CYTARABINE , GEMCITABINE, PURINE ANALOGS 6-MP 6-TG, FLUDARABINE , CLADRIBINE , CLOFARABINE

11. Microtubule damaging agents CLASS EXAMPLE VINKA ALKALOIDS VINCRISTINE, VINBLASTINE, VINORELBINE TAXANES PACLITAXEL, DOCETAXEL, ESTRAMUSTINE

12. MECHANISM OF ACTION

13. Topoisomerase inhibitors CLASS EXAMPLES IA NONE IIB TOPOTECAN , IRINOTECAN IIA ANTHRACYCLINE- DOXORUBICINE,DAUNORUBICIN

14. MECHANISM OF ACTION

15. Antibiotics ACTINOMYCIN D DAUNORUBICIN EPIRUBICIN BLEOMYCIN MITOMYCIN C

16. Miscellaneous HYDROXYUREA L ASPARAGINASE ARSENIC TRIOXIDE

17. Targeted therapy Class Examples TYROSINE PROTEIN KINASE INHIBITOR IMATINIB , NILOTINIB EGF RECEPTOR INHIBITORS GEFTINIB , ERLOTINIB , CETUXIMAB ANGIOGENESIS INHIBITOR BEVACIZUMAB, SUNITINIB PROTEOSOME INHIBITOR BORETEZOMIB UNAMMED MONOCLONAL ANTIBODY TRANTUZUMAB , RITUXIMAB

18. Hormonal agents DRUGS CLASS EXAMPLES GLUCOCORTICOIDS PREDNISOLONE ESTROGENS FOSFESTROL , ETHINYLESTRADIOL SELECTIVE ESTROGEN RECEPTOR MODIFIER TAMOXIFEN, TOREMIFENE SELECTIVE ESTROGEN RECEPTOR DOWNREGULATOR FULVESTRANT AROMATASE INHIBITOR LETROZOLE , ANESTROZOLE , EXEMESTANE ANTIANDROGEN FLUTAMIDE 5 ALPHA REDUCATASE INHIBITOR FINASTERIDE, DUTASTERIDE GNRH ANALOGUE NAFARELIN , LEUPROLIN PROGESTIN HYDROXYPROGESTERONE

19. CHEMOTHERAPY TREATMENT MODALITY Adjuvant chemotherapy Induction chemotherapy Concurrent chemotherapy Palliative chemotherapy Curative intent

20. Induction Chemotherapy Could shrink primary Tumor volume Better blood flow to the tumor Reduce the hypoxic areas within the tumor and make them more radiosensitive Sx and RT treat loco regional disease- Induction CT could address distant metastasis Veteran affair and MACH NC

21. INDUCTION CHEMOTHERAPY Regimen commonly used Cisplatin 100mg/m2 with 5FU 1gm/m2 per day for 4-5 days via infusion bottle 3 cycles Often followed by concurrent chemoradiotherapy (rarely surgery) TAX 323, 324- Docetaxel or paclitaxel

22. Concurrent Chemotherapy Used for the cytotoxic effect and the radiosensitizing effect Reported to have less treatment break ( comparatively lesser toxicity) Most common regimen used is Cisplatin 100mg/m2 at day 1,22,43 of RT With or without 5FU 1g on day1-4

23. Rationale for concurrent CTRT Local antitumor activity of RT is enhanced by the simultaneous CT as radio sensitizer Ct may eradicate possible micro metastasis outside RT field Active against different tumor cell population Decreased tumor cell repopulation following RT fractionation Increase tumor cell recruitment from G0 to RT sensitive phase Improved drug delivery with shrinkage of tumor Less chances of RT/CT resistance

24. Response in Chemotherapy treatment Complete response- Indicative of total tumor regression Partial response- indicative of 50% or greater reduction in the product of the two largest perpendicular diameters of all measurable lesion No response- indicative of no change in the size of the tumour, or less than 50% reduction of all measurable lesion Major response- implies complete or partial response. Minor response- implies less than 50% reduction in the dimensional product

25. CHARACTERESTICS RECIST 1.1 PERCIST 1.0 Measurability of a lesions at baseline Lesions- longest diameter >10mm Lymph nodes; short axis>15mm SUL peak of baseline lesions atleast 1.5 fold greater than liver SUV mean +2 SD. If liver is abnormal, primary tumour should have the uptake >2x SUL mean of blood pool Objective response CR : disappearance of all target lesion PR : Reduction of atleast 30% in the sum of diameter of target lesions PD : Increase of atleast 20% in the sum of diameters of target lesions or appearance of new lesions SD : not CR/PR/PD CMR - complete resolution of 18FDG within all lesions to level of less than or equal to that of mean liver activity and indistuinguishable from the background. PMR - reducation of atleast 30% in SL peak and an absolute drop of 0.8 SL PMD - Increase of atleast 30% in SUL peak and an absolute increase of 0.8 SUL peak units (or)75% increase in TLG with no increase in SUL

26. Common Agents used in HNC Cisplatin 5 FU Cetuximab Geftinib Bevacizumab Nivolumab

27. Platinum bases compound Cisplatin- Di amminedichloroplatinum - Heavy metal platinum- 2 chloride and 2 ammonia molecules in cis position Described by Michele Peyrone in 1844. Its anticancer property was identified by Barnett Rosenberg. USFDA approved for anticancer treatment in 1978

28. Mechanism of action DNA Adduct Formation- N7 position of guanine and adenine to form a variety of monofunctional and bifunctional adducts Ribosome Biogenesis Stress- oxaliplatin’s major cytotoxic impact

29. Cisplatin DNA Adducts- Intra and inter DNA Platinum DNA damage binding protein DNA damage signalling and halt of cell cycle DNA repair

30. Use of cisplatin in head and neck Used in various HPE - sarcoma, carcinoma, lymphoma Used as a induction agent, concurrent agent, palliative agent Dose- 100mg/m2 IV on day 1,22,43 of the RT or 40-50mg/m2 IV weekly for 6-7 weeks

31. Side effects and contraindication Side effects- Nephrotoxicity Neurotoxicity Pancytopaenia Ototoxicity Peripheral neuropathy

32. Side effects and contraindication Contraindication Acute leukemia Severe infection Hypomagnesaemia, hypocalcaemia, hyponatraemia Renal failure, stroke Pregnancy, lactating mother

33. 5 Fluorouracil (5 FU) Antimetabolite Discovered by Heidelberger, Chaudary and Weston in 1950 Mechanism of action – Primarily inhibits thymidylate synthase 5FU will cause the death of rapidly proliferating cancer cells by scarcity of thymidine for DNA synthesis

34. Deoxyuridine monophosphate Deoxy thymidine monophosphate TS

35. Indication of 5 FU Essential component in HNSCC CT ( induction, concurrent, palliative) Can also be used topically for BCC and actinic keratosis Dose- with cisplatin 1000mg/m2/day IV infusion on day 1-4 and 22-25

36. Side effects and contraindication Side effects Myelosupressioon Maculopapular eruptions Cardiotoxicity Mucositis Mood disorder

37. Side effects and contraindications Contraindication Patient with bone marrow suppression Pregnancy Breast feeding

38. Cetuximab Chimeric monoclonal antibody for EGFR May 2000 ImClone reported positive results from stage 1 clinical trials 2006 US FDA approval use in HNSCC as monotherapy and combination MOA- 10 times more affinity to EGFR. Hence blocks the EGFR and growth stimuli and results in cell death

39. Indication in head and neck cancer Initial treatment as monotheraoy with RT Combination with cisplatin in metastatic disease Dose- 400mg/m2 IV infused over 2 hrs maximum 10mg.m2/min (loading) 250mg/m2 maintainence over 60 min once a week

40. Side effects Acneiform rashes Fatigability Hypomagnesaemia Fever chills and nausea Anorexia, abdominal cramps Sever toxicities- fatal bullous mucocutaneous disease, anaphylactic disease Some suggest that the patients who develop rashes are also those who have better tumour response and survival benefit

41. Geftinib Signal transduction inhibitor Mainly used in metastatic HNC MOA- Geftinib selectively inhibits the tyrosine kinase domain and interrupts signal transduction to the nucleus Dose- 250mg once a day (max 500mg) Side effects- skin reactions, diarrhea , anorexia, nausea Interstitial lung disease, corneal erosion, GI perforation

42. Nivolumab Newer monoclonal antibody- Human programmed death receptor-1 (PD-1) FDA approved for melanoma MOA- bind to PD-1 receptors and blocks interaction with PDL1 and PDL2. hence prevents inhibition of immune response In head and neck- Classical non hodgkins lymphoma, melanoma, recurrent/ metastatic disease Side effects- Lymphocytopaenia , hyponatraemia, breath shortness, cough, Loss of appetite, musculoskeletal pain

43. Clinical trials Head and neck contracts programme trial Vetteran affair trial EORTC trial TAX 323, TAX 324 trial Intergroup trial RTOG trial Bonner trial Induction CT Concurrent CT Targeted therapy

44. Head and neck contracts programme

45. Veterans affairs trail

46. European organization for research and treatment of cancer EORTC

47. Tax 323 and tax 324

48. Intergroup trial

49. RTOG-91-11 trial

50. Bachaud et al CTRT trial

51. RTOG 95 01

52. EORTC 22931

53. Bonner trial

54. Chemoprevention Use of natural or synthetic chemical for the reversal, suppression or prevention of conversion premalignant lesion to invasive forms. Chemopreventive agents used- Retinoids and vitamin A Vitamin E Selenium, cyclo oxygenase2 inhibitors Tyrosine kinase inhibitors ONYX 015, Protease inhibitors

55. Summary Concurrent chemoradiotherapy is at present the standard of care for treatment of locally advanced head and neck cancer with a confirmed absolute survival benefit of 6.5% at 5 years. Single agent cisplatin, which in the past has been shown to be as effective as multiple drug regimes, is now being challenged by the introduction of the use of taxanes . Targeted biological agents, such as cetuximab , have a role to play in both advanced head and neck cancer and recurrent or metastatic disease but those roles are still being established.

56. Reference Scott brown 8 th edition Jatin shah head and neck surgery and oncology DeVita Cancer principle and practice of oncology